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MSS 2 > Principles of Autoimmunity > Flashcards

Principles of Autoimmunity Flashcards

1
Q

What is autoimmunity?

A
  • reaction against self antigens.

- diseases can be organ-specific or systemic

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2
Q

Can autoantibodies be found in healthy individuals?

A
  • YES (particularly the aged).

* may be formed in response to release of cryptic (intracellular) antigens occurring during cell injury.

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3
Q

What are the 3 requirements of pathologic autoimmunity?

A
  1. presence of an autoimmune reaction.
  2. evidence that the reaction is NOT secondary (aka it is primary) to tissue damage, but instead is of primary importance in pathogenesis.
  3. absence of another, well-defined cause of the disease.
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4
Q

What cell type primarily drives autoimmune disorders?

A
  • T CELLS and/or ANTIBODIES directed against self antigens.
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5
Q

What are some ORGAN SPECIFIC autoimmune diseases?

A
  • autoimmune hemolytic anemia (antibody)
  • MS (T cells)
  • goodpastures (antibody)
  • autoimmune thrombocytopenia (antibody)
  • T1DM (T cells)
  • myasthenia gravis (antibody)
  • graves disease (antibody)
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6
Q

What are some SYSTEMIC autoimmune diseases?

A
  • systemic lupus erythematosus (antibody)
  • rheumatoid arthritis (T cells and antibody)
  • sjogren syndrome (T cells)
  • systemic sclerosis (scleroderma; T cells)
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7
Q

** From what does autoimmunity result?

A
  • a breakdown in self-tolerance
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8
Q

What are the 2 general pathways of autoimmunity?

A
  1. susceptibility genes leading to failure of self-tolerance.
  2. environmental trigger (infections) activating self-reactive lymphocytes
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9
Q

What is immunologic tolerance?

A
  • a state in which the individual is incapable of developing an immune response to a specific antigen.
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10
Q

*** What are the 2 mechanisms for SELF TOLERANCE?

A
  1. CENTRAL tolerance= occurs during lymphocyte maturation in the primary lymphoid organs; all cells pass through a stage in which encounter with an antigen leads to cell death, receptor editing, or anergy.
  2. PERIPHERAL tolerance= occurs when mature lymphocytes that recognize self antigens, become incapable of responding to that antigen, lose viability or are induced to die via apoptosis.
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11
Q

What are the 3 important events in the development of B and T lymphocytes?

A
  1. commitment of progenitor cells to the B or T cell lineage.
  2. Temporally ordered process of rearrangement of antigen receptor genes and expression of antigen receptor proteins.
  3. selection events that preserve cells that have produced correct antigen receptor proteins and elimination events to remove potentially dangerous cells.
    * these developmental checkpoints ensure that all mature lymphocytes express functional receptors with useful (and not deleterious) specificities.
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12
Q

Where does central tolerance occur?

A
  1. Bone marrow (B lymphocytes)

2. Thymus (T lymphocytes)

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13
Q

What are the mechanisms of CENTRAL tolerance?

A
  • double positive T cells with high affinity T cell receptor for self antigen are deleted (NEGATIVE selection) via apoptosis.
  • clonal deletion is also operative in developing B cells= developing B cells (IgM+ IgD-) encounter membrane bound antigen in the bone marrow.
  • clonal deletion is not foolproof bc many self antigens are still not expressed in the bone marrow and/or thymus.
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14
Q

At what stage of B cell maturation does negative selection (central tolerance) occur?

A
  • IMMATURE B CELL (after pro- and pre-B cell development, but before mature B cell stage) in the BONE MARROW.
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15
Q

At what stage of T cell maturation does positive and negative selection occur?

A
  • between DOUBLE POSITIVE and SINGLE POSITIVE (immature T cell) development in the THYMUS.
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16
Q

Is anergy a mechanism of central or peripheral tolerance?

A
  • PERIPHERAL.
  • It is defined as the prolonged or irreversible functional inactivation of lymphocyte or as a state of unresponsiveness to antigenic stimulation.
17
Q

Where are almost all antigens in the body going to be expressed?

A
  • medulla of the thymus

* aka where we are going to show all the self-antigens

18
Q

What is the role of the thymus?

A
  • clonal deletion
  • development of multiple populations of cells responsible for maintaining peripheral tolerance (dendritic and T regulatory cells).
19
Q

How do PERIPHERAL antigens that are not normally expressed in primary lymphoid organs get to those organs to participate in negative selection processes?

A
  • AIRE (AutoImmune REgulator)= stimulates the expression of many “peripheral” self-antigens in the thymus (specifically medullary thymic epithelial cells (mTECs).
  • AIRE is critical for deletion of immature self reactive T cells in the thymus.
20
Q

What do mutations of AIRE cause?

A
  • autoimmune polyendocrinopathy
21
Q

May anergy occur if the antigen is presented to a T cell without the APC cell expressing CD80/86 (B7 1/2)?

A
  • YES

* anergy is a TEMPORARY phenomenon and long term requires re-engagement.

22
Q

How else can we create an anergic state? (aka maintain peripheral tolerance)

A
  • CTLA-4= competes with CD28 for B7 binding. When CTLA-4 binds to B7 (CD80/86), the T cell receives a down regulatory signal.
  • PD-1= ligands on dendritic cells
23
Q

What are Foxp3-expressing CD4 T cells?

A
  • T regulatory cells (Tregs). These cells suppress immune responses through numerous mechanisms: anti-inflammatory cytokines, direct cell-cell contact, or by modulating the activation of APCs.
24
Q

What controls T cell activation?

A
  1. engagement with MHC
  2. CD28 (T cell) engagement with CD80/86 (B7; APC).
    * leads to activation of immune response.
25
Q

How do regulatory T cells prevent autoimmune reactions?

A
  1. they arise in the THYMUS as a result of recognition of self antigen -OR- arise in peripheral lymphoid organs.
  2. produce cell surface markers (CTLA-4 or PD-1) to down regulate T cells. Also gene product Foxp3.
  3. generation of IL-10 and TGF-B, which down-regulate the immune response.
26
Q

What are the most abundant T regulatory cells?

A
  • CD4+

- CD25+

27
Q

How do we delete activated T cells?

A
  • Fas (TNF receptor): FasL (TNF homolog on T cells) interaction triggers death-inducing signaling complex (DISC), in turn activating caspases leading to cell death.
  • pro-apoptotic proteins such as Bim= induce apoptosis via mitochondrial intrinsic pathway.
28
Q

What is antigen sequestration?

A
  • some antigens are hidden from the immune system in tissues that do not communicate fully with blood and lymph (TESTES, EYES, and BRAIN).
  • aka immunologically privileged sites.
29
Q

What is a specific susceptibility gene involved in ankylosing spondylitis?

A
  • HLA-B27
30
Q

What gene is most frequently implicated in RA and T1DM?

A
  • PTPN (tyrosine phosphatase)
31
Q

What is the role of infection in autoimmunity?

A
  • up-regulation of co-stimulatory molecules on APCs. If these cells present self antigen, the result may be breakdown of clonal anergy and activation of self-reactive T cells.
  • some microbes may express antigens that have the same amino acid sequences as self antigens leading to cross-reactive lymphocytes (known as molecular mimicry).
32
Q

What is a great example of molecular mimicry?

A
  • group A strep leading to cross-reactive T lymphocytes attacking the heart; rheumatic heart disease
33
Q

How can cell injury lead to autoimmunity?

A
  • release of intracellular self-antigens that activate non-tolerant lymphocytes, leading to cytokine production (esp. in privileged sites).
34
Q

What is epitope spreading?

A
  • infections or the initial autoimmune reaction causing the release of other self antigens or the alteration of self antigen, or expose antigens that are normally concealed from the immune system (cryptic antigens). This results in the continued activation of new self reactive lymphocytes.
35
Q

Do hormones influence autoimmune diseases?

A
  • females seem to be more susceptible.

MSS 2 (15 decks)

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